Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP 4 receptor

Tatsuya Hoshino, Takushi Namba, Masaya Takehara, Naoya Murao, Takahide Matsushima, Yukihiko Sugimoto, Shuh Narumiya, Toshiharu Suzuki, Tohru Mizushima

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Amyloid-β peptide (Aβ), which is generated by the β- and γ-secretase-mediated proteolysis of β-amyloid precursor protein (APP), plays an important role in the pathogenesis of Alzheimer's disease (AD). We recently reported that prostaglandin E 2 (PGE 2) stimulates the production of Aβ through both EP 2 and EP 4 receptors and that activation of the EP 4 receptor stimulates Aβ production through endocytosis and activation of γ-secretase. We here found that transgenic mice expressing mutant APP (APP23) mice showed a greater or lesser apparent cognitive deficit when they were crossed with mice lacking EP 2 or EP 4 receptors, respectively. Mice lacking the EP 4 receptor also displayed lower levels of Aβ plaque deposition and less neuronal and synaptic loss than control mice. Oral administration of a specific EP 4 receptor antagonist, AE3-208 to APP23 mice, improved their cognitive performance, as well as decreasing brain levels of Aβ and suppressing endocytosis and activation of γ-secretase. Taken together, these results suggest that inhibition of the EP 4 receptor improves the cognitive function of APP23 mice by suppressing Aβ production and reducing neuronal and synaptic loss. We therefore propose that EP 4 receptor antagonists, such as AE3-208, could be therapeutically beneficial for the prevention and treatment of AD.

Original languageEnglish
Pages (from-to)795-805
Number of pages11
JournalJournal of Neurochemistry
Volume120
Issue number5
DOIs
Publication statusPublished - 2012 Mar

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Amyloid Precursor Protein Secretases
Genetic Models
Cognition
Alzheimer Disease
Amyloid beta-Protein Precursor
Chemical activation
Pharmacology
Proteolysis
Endocytosis
Prostaglandins E
Amyloid
Brain
Mutant Proteins
Transgenic Mice
Oral Administration
Inhibition (Psychology)
4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid

Keywords

  • aging
  • Alzheimer disease
  • infammation
  • memory
  • neurodegeneration

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP 4 receptor. / Hoshino, Tatsuya; Namba, Takushi; Takehara, Masaya; Murao, Naoya; Matsushima, Takahide; Sugimoto, Yukihiko; Narumiya, Shuh; Suzuki, Toshiharu; Mizushima, Tohru.

In: Journal of Neurochemistry, Vol. 120, No. 5, 03.2012, p. 795-805.

Research output: Contribution to journalArticle

Hoshino, T, Namba, T, Takehara, M, Murao, N, Matsushima, T, Sugimoto, Y, Narumiya, S, Suzuki, T & Mizushima, T 2012, 'Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP 4 receptor', Journal of Neurochemistry, vol. 120, no. 5, pp. 795-805. https://doi.org/10.1111/j.1471-4159.2011.07567.x
Hoshino, Tatsuya ; Namba, Takushi ; Takehara, Masaya ; Murao, Naoya ; Matsushima, Takahide ; Sugimoto, Yukihiko ; Narumiya, Shuh ; Suzuki, Toshiharu ; Mizushima, Tohru. / Improvement of cognitive function in Alzheimer's disease model mice by genetic and pharmacological inhibition of the EP 4 receptor. In: Journal of Neurochemistry. 2012 ; Vol. 120, No. 5. pp. 795-805.
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